School of medicine symptoms and conditions

Why does Singulair cause these symptoms? I am going to give my explanation which is only a HYPOTHESIS. This should not be categorized as any thing but an educated guess. This is not backed by scientific research because nobody will do any research that would appear to anger
Merck even if people are suffering in the thousands.

1. The original research that preceded the development of Singulair (montelukast) seemed to focus on the theory that asthma was caused by an unusual immune response to certain pathological stimulus. There are many references to the observation that a high percentage of asthma sufferers are people whose asthma is caused by fungus. Many people suffer from asthma and are told that they are allergic to dust mites. Dust mites can live only because the fungus aspergillus pre-digests the
food source that dust mites can then absorb. Other sources of fungus occur in the home due to dampness or problems with wood rot.

2. The body's immune system fights certain categories of pathogens such as bacteria and fungus by creating nitric oxide which kills them at the site where they try to enter the body. The mast cell is the immune cell that is responsible for the production of nitric oxide. Mast cells are found in the skin, airways, intestines etc. The mast cell is capable of many different types of biochemical functions that are designed to signal other cells or other chemical responses. When the mast cell knows that pathogens
are present and nitric oxide is NOT produced, then it signals other immune cells to be sent to the site of the infection. Thus in the case of asthma, it is known that excessive numbers of eosinophils appear in the airways and these cells create inflammation.

3. Singulair was developed for asthma and later allowed to be prescribed for other reasons. I believe that montelukast probably creates a source of nitric oxide that prevents the mast cell from signalling for other immune cells to arrive at the source of infection. I arrived at that conclusion from studying the chemical structure of montelukast, the chemical structure of the gene cysLT1 receptor, and the chemical structure of the cell wall of fungus which would be what the mast cell uses to determine "what to do in order to kill the fungus."

The researchers who invented montelukast first had to clone the gene-cysLT1 receptor meaning that they had to be able to identify the gene and replicate it. Then by trial and error they had a find a "chemical"
that would bind (connect chemically) to the cysLT1 receptor. The theory would be that montelukast would take the place of the fungus or other pathogen and thus prevent the gene from reacting to produce the
responses that the sick patient with asthma produced. Merck says in the literature that montelukast binds with the cysLT1 receptor in order to prevent the mast cell from signalling the eosinophils to arrive in excessive
numbers that cause inflammation. I believe that montelukast is also causing the production of an amount of nitric oxide that is actually killing the pathogens that are present. For one thing, I would think that it
would be dangerous to incapacitate the immune system in that way without providing a way to kill the pathogens. I don't believe that the asthma response is just allergies to something like dust. Pollen from trees and flowers is loaded with fungus spores.

4. IF, IF, IF, montelukast does actually produce nitric oxide, then it does so by binding with the gene. Any place in the body where a molecule of montelukast encounters the cysLT1 receptor (a gene) then the corresponding molecules of nitric oxide are produced before the liver enzymes break the montelukast molecules up. Nitric oxide is TOXIC and
INFLAMMATORY. So let's look at the symptoms in regard to the location of the cysLT1 receptors. The location of these symptoms would not be places in the body where the mast cells normally encounter fungus or bacteria. The cysLT1 also has other functions in that it communicates with the cysLT2 receptors. Obviously, nitric oxide
should not be produced in these locations because of the signalling effect of nitric oxide on other physiological functions.

a. intestinal pain - the cysLT1 receptors are located in the small intestines
b. leg pain actually caused by vasculitis - cysLT1 receptors are found inside blood vessels- consistent with the fact that montelukast causes
Churg-Strauss
c. some people who didn't have asthma develop asthma - the cysLT1 receptors are in the airways
d. nightmares, depression, neurological damage - when montelukast penetrates the blood brain barrier probably due to unusual conditions of blood pH or electrolyte imbalance then nitric oxide in the brain causes neuron damage and excitoxicity

5. Why do some patients not experience side effects? Probably because genetically they are completely compatible with the model that researchers created when they cloned the cysLT1 receptor gene. I didn't not find any information about whether researchers knew that there are many different variations of this gene.

6. IF, my theory is even close to being correct, then why doesn't Merck do anything about researching these side effects. Maybe because nobody in the company knows how this drug works but the researchers who created it. All of the Merck literature is very vague about any biochemical information.

Again, this is just speculation and hypothesis. I have made an attempt to put this in simplistic language and therefore sacrifice scientific accuracy. But, I think that you will get the point.

SINGULAIR IS VERY DANGEROUS TO PATIENTS WHO EXPERIENCE NEGATIVE SIDE EFFECTS. DOCTORS SHOULD JUST REALIZE THAT
THOSE PATIENTS ARE NOT COMPATIBLE WITH THE MODEL FOR THE DRUG.

The Journal of Immunology, Vol 146, Issue 4 1294-1302, Copyright © 1991 by American Association of Immunologists

ARTICLES
Urinary nitrate excretion in relation to murine macrophage activation. Influence of dietary L-arginine and oral NG-monomethyl-L-arginine

DL Granger, JB Hibbs Jr and LM Broadnax
Division of Infectious Diseases, Duke University School of Medicine, Durham, NC 27710.

Murine macrophage oxidation of L-arginine guanidino nitrogen to nitrite/nitrate yields an intermediate effector, possibly nitric oxide, with antimicrobial activity. Total body nitrogen oxidation metabolism (NOM) was measured in vivo by determining the urinary nitrate excretion of mice ingesting a chemically defined nitrite/nitrate-free diet. As reported previously, mycobacterial infection with bacillus Calmette- Guerin led to a large increase in urinary nitrate excretion. This increase was temporally related to macrophage activation in vivo. The substrate for macrophage nitrogen oxidation metabolism in vitro, L- arginine, was deleted from the diet without ameliorating the urinary nitrate excretion response induced by BCG. This suggested that L- arginine was synthesized endogenously because there are no other known natural substrates for NOM. A competitive inhibitor of NOM, the L- arginine analog, NG-monomethyl-L-arginine was fed to mice in their drinking water. NG-monomethyl-L-arginine ingestion blocked both basal and bacillus Calmette-Guerin-induced urinary nitrate excretion over a 2- 4 week time span. These experimental conditions should prove useful for further investigation on the role of macrophage NOM in host defense against intracellular microorganisms.

I discovered this site last Wednesday morning - without taking the time to list all of the grief I felt reading through the pediatric postings, I will briefly note my 4 year old daughter has been on Singulair for 2 years now. What I now realize is all the behavior issues, night screaming, etc. are so easily dismissed as stages of a toddler. She has suffered (as well as our family) every symptom and behavior listed by parents on this site with the exception of leg cramps.

Our entire family can see the dramatic results since taking her last pill last Tuesday night. The melt downs and tantrums are all but over, she even commented "hey, I listened right away" on the second day without Singulair. She is still having night terrors - I call them that because they are in no way a dream or nightmare, but rather agonizing moments that break our hearts to hear. I hope those will soon go away as well so her sleep pattern results in a restful night.

Am I angry that we have all suffered for 2 years only to find we have been basically poisoning her? Am I angry that for the 2 years her dad and I have sunk pretty low, feeling inadequate as a parent to teach and discipline our child? Am I angry that after 20 years of marriage, raising a great 16 year old in the midst of all this, we were to the point of the ADD, bipolar, etc. theory that would have been misdiagnosed? Heck no, we are all so thankful to have come across this site and are so giddy and excited to be happy again.

What I am angry about is this - when I called our pediatrician last Wednesday and relayed what I had seen on the Merck website for side effects added in recent months she had not heard this information and asked where I saw it. At that point I had not seen this site. I asked her how is it the well dressed pharmaceutical reps come in with doughnuts, exotic trips, etc. to market a drug with "ABC" treatments and "XYZ" side effects, continue to market the drug and never update the doctors when original selling points are altered - ie; new side effects.

The FDA website is troubling for two reasons: Merck is in charge of their own investigation regarding recent complaints and the FDA expects this to take 9 months. Gee, who gets to investigate themself? Secondly, in February the site notes the FDA and Merck are trying to find the best way to communicate the concerns being investigated to prescribes and patients. HELLO - we live in a world of real time, instant communication methods, two examples being the United States Postal Service and an internet connection.

Today is April 30 - a full two months after "trying to decide how to pass this information on" and my doctor, nor my pharmacist have received any information. Apparantly since we missed the story and coverage on Dateline we are out of luck.

I plan to start from ground zero to get our voices heard to change the way, or the law if you will, to implement an immediate communication link between the FDA and prescribes when an investigation such as this has been initiated. I realize Singulair has most likely benefited more humans than it has destroyed while on the drug and the FDA would have to clearly not communicate "panic". However, when a drug is used for pediatric treatments we need information quickly to assess on behalf of our children. In my case, since my daughter had been on the drug since 2 years old, I do not know what her "normal behavior" should be as that is the age they start to develop and show personality. Additionally, when enclosed prescribing information is updated with a prescription -MARK IT IN RED, "UPDATED INFORMATION". I read every ounce of information that accompanies a new prescription for any family member. I would NOT, however read the information every 30 days for an ongoing, long term prescription over the course of 2 years.

I am looking for anyone that may have started contact with a congressional representative or otherwise to change the communication to our doctors. Please note - I am in no way interested in any legal action regarding Singulair and our nightmare. We are moving forward and do not wish to live the nightmare one moment more. I simply want to see our doctors and pharmacists have vital information as it happens.

Thank you to all for sharing your experiences - I truly believe it is changing lives and making a difference. I am personally telling everyone I know about what is happening with our child and all of yours. Andy by the way, by telling one of my long time friends our amazing discovery, she realized she had been suffering from depression for some time and chalked it up to various things going on in her life. She had her last Singulair last week and feels tremendous! So keep the word going!

Singulair does interact with the astrocyte in the brain.

The role of the cysLT1 receptor (Singulair blocks this receptor) and the astrocyte in the brain has been studied. For anyone from Merck to say that there are no mechanisms by which Singulair can affect the
brain is ludicrous. If the Chinese researchers are correct, then Singulair very clearly affects the brain. Certainly, we don't know exactly how or when the effect would be good or bad. Under what circumstances would it be beneficial and under what circumstances would it be harmful.

For quite a while, researchers have been hypothesizing about the role of the astrocyte in brain function. If we go to look for theories, we will find them. Here is the theory of Dr. Dale Antanitus. I am no here to promote anyone's theory in particular but just to point out that they exist.

http://www.antanitus.com/hypothesis

We can see that the Chinese researchers have gone forward to look at potential links between the cysLT1 receptor (Singulair receptor) and inflammatory response in the brain. The 2008 study showed a link between the astrocyte and the cysLT1 receptor (Singulair receptor)

1: Glia. 2008 Jan 1;56(1):27-37. Links
Activation of CysLT receptors induces astrocyte proliferation and death after oxygen-glucose deprivation.

Huang XJ, Zhang WP, Li CT, Shi WZ, Fang SH, Lu YB, Chen Z, Wei EQ.
Department of Pharmacology, School of Medicine, Zhejiang University, Hangzhou 310058, People's Republic of China.

We recently found that 5-lipoxygenase (5-LOX) is activated to produce cysteinyl leukotrienes (CysLTs), and CysLTs may cause neuronal injury and astrocytosis through activation of CysLT(1) and CysLT(2) receptors in the brain after focal cerebral ischemia. However, the property of astrocyte responses to in vitro ischemic injury is not clear; whether 5-LOX, CysLTs, and their receptors are also involved in the responses of ischemic astrocytes remains unknown. In the present study, we performed oxygen-glucose deprivation (OGD) followed by recovery to induce ischemic-like injury in the cultured rat astrocytes. We found that 1-h OGD did not injure astrocytes (sub-lethal OGD) but induced astrocyte proliferation 48 and 72 h after recovery; whereas 4-h OGD moderately injured the cells (moderate OGD) and led to death 24-72 h after recovery. Inhibition of phospholipase A(2) and 5-LOX attenuated both the proliferation and death. Sub-lethal and moderate OGD enhanced the production of CysLTs that was inhibited by 5-LOX inhibitors. Sub-lethal OGD increased the expressions of CysLT(1) receptor mRNA and protein, while moderate OGD induced the expression of CysLT(2) receptor mRNA. Exogenously applied leukotriene D(4) (LTD(4)) induced astrocyte proliferation at 1-10 nM and astrocyte death at 100-1,000 nM. The CysLT(1) receptor antagonist montelukast attenuated astrocyte proliferation, the CysLT(2) receptor antagonist BAY cysLT2 reversed astrocyte death, and the dual CysLT receptor antagonist BAY u9773 exhibited both effects. In addition, LTD(4) (100 nM) increased the expression of CysLT(2) receptor mRNA. Thus, in vitro ischemia activates astrocyte 5-LOX to produce CysLTs, and CysLTs result in CysLT(1) receptor-mediated proliferation and CysLT(2) receptor-mediated death. (c) 2007 Wiley-Liss, Inc.

PMID: 17910051

The astrocyte has been studied to see how it functions in the brain. The astrocyte:

1. may perform a role in the physical structuring of the brain
2. may perform a role in providing neurons with nutrients
3. may perform a minor role in the maintenance of the blood brain barrier
4. may perform a role in neurotransmitters
5. may perform a role in the regulation of ion concentration in the extracellular spaces
6. may perform a role in neuronal regulation of blood flood
7. may perform a role in the protection and repair of neurons

TO LIE TO PEOPLE REGARDING THEIR HEALTH IS CRIMINAL AND SHOULD BE PROSECUTED. PEOPLE OUT THERE ARE GETTING SICKER IF THEY ARE EXPERIENCING SIDE EFFECTS BECAUSE MERCK IS LYING. SOME PEOPLE MAY NOT EXPERIENCE SIDE EFFECTS BUT WHY NOT TELL THE TRUTH AND SAY THAT THERE COULD BE SOME PEOPLE WHO HAVE PSYCHIATRIC SIDE EFFECTS BECAUSE THERE IS A PATHWAY FOR THAT TO HAPPEN.

Here is another who might know how to help.

I got stuck on trying to understand IgE. Here is somebody else who might know something.

Immunol Res. 2007;37(1):1-16.Links
Decoding IgE Fc receptors.Zhang M, Murphy RF, Agrawal DK.
Department of Medical Microbiology and Immunology, Creighton University School of Medicine, Omaha, NE 68178, USA.

Immunoglobulin E (IgE) plays a central role in the pathogenesis of allergic diseases by interacting with two membrane receptors: high-affinity FcepsilonRI and low-affinity FcepsilonRII (CD23). Allergeninduced IgE-occupied FcepsilonRI aggregation on the mast cell or basophil cell surface leads to the activation of intracellular signaling events and eventually the release of pre-formed and de novo synthesized inflammatory mediators. The role of FcepsilonRII in allergic diseases has been proposed to include regulation of IgE synthesis, enhanced histamine release from basophils, and a contribution to Ag-IgE complex presentation but the exact function of CD23 remains poorly understood. This review summarizes some new developments in IgE Fc-receptor studies with an emphasis on regulation of FcepsilonRI expression and signal transduction, including monomeric IgE, lipid raft segregation, and some recently identified negative regulators. A better understanding of signaling events following IgE FcR aggregation will shed new light on how allergy patients might be treated more safely and effectively.

I know that many here would like the FDA to take a very serious took at the problem. I personally don't see how a review of their data is going to make any difference at all. But, if there are experts who can propose a model of the pathways of cell signalling that include the possibility that these symptoms can occur (and under what circumstance), then maybe the problem will look like something much more than statistics.

This is not my field. But I tried to follow the possible pathways to see if I could identify a possible area of concern. Then I looked for someone who had written in the area and read their abstract. A place to start may be to get an opinion from those who know something about "normal homeostasis of the mast cell." Singular blocks the cysteinyl leukotriene receptor 1 which is a site on the outer membrane of the mast cell (other cells also). The mast cell which is produced in the bone marrow is released in a immature state and matures after it arrives at it's destination. The mast cell does not become active unless it's receptor sites come in contact with the activating agent. So, what happens when a receptor site on the mast cell is suppressed by Singular, a receptor antagonist.

You see, I don't have a clue what the signals are that tell the bone marrow to make mast cells (or what the signals are that tell them where to go after they are made in the bone marrow). Does Singular interfere with something that tells the bone marrow what to do? If Singular does interfere with that process, then what is happening and what period of time does it take to happen? Could we wonder whether Singular is interfering with the NUMBER of mast cells that are produced over time? And, of course, maybe there is some OTHER kind of explanation for why the adverse drug reactions are happening. But, at this level, I got lost and can't go any further.

Maybe this group would be interested in the Singulair problems or could suggest somebody else?

http://www.edata-center.com/journals/2ff21abf44b19838,0a1257122f661a7e,0d8ee7116ef23452.html

I apologize if this lead doesn't produce any results but at least it could be a place to start.

(I posted this before but after receiving some e-mail, I have revised a few sentences to hopefully make it more understable. )

I would like to share this information with everyone. First, I would like to caution all that it does not prove anything regarding the negative side effect of Singulair but it does suggest that there might (only might) be a physiological cause for any side effect that could be attributed to brain function. A Chinese team has been studying the receptor (Cysteinyl leukotrienes receptor 1) that is targeted by Singulair and is responsible for the method of action that makes Singulair successful. Here is one of their studies.

1: Neurosci Lett. 2004 Jun 17;363(3):247-51. Links Expression of cysteinyl leukotriene receptor 1 in human traumatic brain injury and brain tumors.Zhang WP, Hu H, Zhang L, Ding W, Yao HT, Chen KD, Sheng WW, Chen Z, Wei EQ. Department of Pharmacology, School of Medicine, Zhejiang University, 353, Yan An Road, Hangzhou 310031, PR China. Cysteinyl leukotrienes (CysLTs) are potent proinflammatory mediators. CysLT receptor 1 (CysLT(1)) is one of the two CysLT receptors that has been cloned. Although the expression of CysLT(1) in the brain has been demonstrated by Northern blot and RT-PCR analyses, the location of CysLT(1) in the brain remains unknown. The objective of this study was to examine the distribution of CysLT(1) by immunohistochemical analysis in human brains with traumatic injury or tumors. CysLT(1) was expressed intensely in the microvascular endothelial cells in both normal and abnormal conditions. At 8 days after traumatic injury, microvascular regeneration was found and all of the endothelial cells highly expressed CysLT(1). In gray and white matters of the normal regions of the brain, CysLT(1) was expressed weekly or not at all. However, the CysLT(1) expression increased in the neuron- and glial-appearing cells in gray and white matters after traumatic brain injury. CysLT(1) was also detected in astrocytoma, ganglioglioma and metastatic adenocarcinoma, and the expression in the neuron- and glial-appearing cells around brain tumors increased robustly. PMID: 15182953

Here is the relevant part of the study. "Although the expression of CysLT(1) in the brain has been demonstrated by Northern blot and RT-PCR analyses, the location of CysLT(1) in the brain remains unknown." That sentence says that these scientists believe that CysLT1 exists in the brain but they did not know what the location in the brain was. Then they did this study which showed that the receptor existed in the tissues of the brain that are listed above and are too complicated to discuss here.

It is logical to assume that if a receptor exists in any part of the body that it has a function in other words it does something or tells some other part of the body to do something. They have not proved (that takes many studies) what part of the brain or what the receptor does in the brain or what the effect on the body is if the receptor does not do it's job. We do know that Singular (montelukast, Cysteinyl leukotriene receptor 1 antagonist) blocks this particular receptor so if the receptor exists in the brain that it COULD BE POSSIBLE that Singular prevents this receptor in the brain from doing it's job whatever that is. I know that it is difficult to argue with doctors. This drug has been around a long time. It would be difficult to understand why we are just learning about problems after so long a period of time. I can see from all of these responses that these problems are very real. Of course, we have no idea if Singulair is related or not. But if you need something supportive to show that it is not impossible for them to be related even though there is no proof that they are related, you could print this out and discuss it with your doctor.

This isn't proof of anything but at least it might be a clue. It just shows that it is not impossible that Singular affects brain function in some way.

I would like to share this information with everyone. First, I would like to caution all that it does not prove anything regarding the negative side effect of Singulair but it does suggest that there might (only might) be a physiological cause for any side effect that could be attributed to brain function.

A Chinese team has been studying the receptor (Cysteinyl leukotrienes receptor 1) that is targeted by Singulair and is responsible for the method of action that makes Singulair successful. Here is one of their studies.

1: Neurosci Lett. 2004 Jun 17;363(3):247-51. Links
Expression of cysteinyl leukotriene receptor 1 in human traumatic brain injury and brain tumors.Zhang WP, Hu H, Zhang L, Ding W, Yao HT, Chen KD, Sheng WW, Chen Z, Wei EQ.
Department of Pharmacology, School of Medicine, Zhejiang University, 353, Yan An Road, Hangzhou 310031, PR China.

Cysteinyl leukotrienes (CysLTs) are potent proinflammatory mediators. CysLT receptor 1 (CysLT(1)) is one of the two CysLT receptors that has been cloned. Although the expression of CysLT(1) in the brain has been demonstrated by Northern blot and RT-PCR analyses, the location of CysLT(1) in the brain remains unknown. The objective of this study was to examine the distribution of CysLT(1) by immunohistochemical analysis in human brains with traumatic injury or tumors. CysLT(1) was expressed intensely in the microvascular endothelial cells in both normal and abnormal conditions. At 8 days after traumatic injury, microvascular regeneration was found and all of the endothelial cells highly expressed CysLT(1). In gray and white matters of the normal regions of the brain, CysLT(1) was expressed weekly or not at all. However, the CysLT(1) expression increased in the neuron- and glial-appearing cells in gray and white matters after traumatic brain injury. CysLT(1) was also detected in astrocytoma, ganglioglioma and metastatic adenocarcinoma, and the expression in the neuron- and glial-appearing cells around brain tumors increased robustly.

PMID: 15182953

Here is the relevant part of the study.

"Although the expression of CysLT(1) in the brain has been demonstrated by Northern blot and RT-PCR analyses, the location of CysLT(1) in the brain remains unknown."

That sentence says that these scientists believe that CysLT1 exists in the brain but they don't know what the location in the brain is.

It is logical to assume that if a receptor exists in any part of the body that it has a function in other words it does something or tells some other part of the body to do something. So we don't know what part of the brain or what the receptor does in the brain or what the effect on the body is if the receptor does not do it's job.

We do know that Singular (montelukast, Cysteinyl leukotriene receptor 1 antagonist) blocks this particular receptor so if the receptor exists in the brain that it COULD BE POSSIBLE that Singular prevents this receptor in the brain from doing it's job whatever that is.

I know that it is difficult to argue with doctors. This drug has been around a long time. It would be difficult to understand why we are just learning about problems after so long a period of time. I can see from all of these responses that these problems are very real. Of course, we have no idea if Singulair is related or not. But if you need something supportive to show that it is not impossible for them to be related even though there is no proof that they are related, you could print this out and discuss it with your doctor.

This isn't proof of anything but at least it might be a clue.